Proteins, which
perform such vital roles in our bodies as building and
maintaining tissues and regulating cellular processes, are a
finicky lot. In order to work properly, they must be folded just
so, yet many proteins readily collapse into useless tangles when
exposed to temperatures just a few degrees above normal body
temperature.

This precarious stability
leaves proteins and the living beings that depend upon them on
the edge of a precipice, where a single destabilizing change in a
key protein can lead to disease or death. It also greatly
complicates the manufacture and use of proteins in research and
medicine.

Finding a way to stabilize
proteins could help prevent such dire consequences, reduce the
very high cost of protein drugs and perhaps also help scientists
understand why proteins are often so unstable in the first place.
In a paper published in the Dec. 11 issue of the journal
Molecular Cell, researchers at the University of Michigan
and the University of Leeds describe a new strategy for
stabilizing specific proteins by directly linking their stability
to the antibiotic resistance of bacteria.

"The method we developed
should provide an easy way to strengthen many proteins and by
doing so increase their practical utility," said James
Bardwell, a Howard Hughes Medical Institute investigator and
professor of molecular, cellular and developmental biology at
U-M.

In the new approach, the
researchers found that when a protein is inserted into the middle
of an antibiotic resistance marker, bacterial antibiotic
resistance becomes dependent upon how stable the inserted protein
is. This enabled the scientists to easily select for stabilizing
mutations in proteins by using a simple life-or-death test for
bacterial growth on antibiotics. The mutations the scientists
identified rendered proteins more resistant to unfolding.

"This method also has
allowed us to catch a glimpse of why proteins may need to be just
barely stable," said Linda Foit, the graduate student at U-M
who initiated the work. "The mutations that we found to
enhance the stability of our model protein are mostly in key
areas related to the protein's function, suggesting that this
protein may need to be flexible and therefore marginally stable
in order to work. It may be that, over the course of evolution,
natural selection acts to optimize, rather than maximize protein
stability."

The work was conducted in the
laboratories of Bardwell at U-M and Sheena Radford at the
University of Leeds and spearheaded by Foit in Bardwell's lab and
postdoctoral fellow Gareth Morgan in the Radford lab. In addition
to these researchers, the paper's authors are U-M undergraduate
students Maximilian Kern, Lenz Steimer and Anne Kathrin von Hacht
and Leeds technician James Titchmarsh and senior lecturer Stuart
Warriner. The research was funded in part by the Howard Hughes
Medical Institute, the National Institutes of Health, the
Wellcome Trust and the University of Leeds.